Abstract

OBJECTIVE:

To determine whether use of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.

DESIGN:

Population based cohort study.

SETTING:

General practices contributing data to the UK Clinical Practice Research Datalink.

PARTICIPANTS:

154 162 adults newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2017, followed until 31 March 2018.

MAIN OUTCOME MEASURES:

Use of DPP-4 inhibitors and GLP-1 receptor agonists was modelled as a time varying variable and compared with use of other second or third line antidiabetic drugs. All exposures were lagged by one year to account for cancer latency and to minimise reverse causality. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of incident cholangiocarcinoma associated with use of DPP-4 inhibitors and GLP-1 receptor agonists, separately. A post hoc pharmacovigilance analysis was conducted using the World Health Organization's global individual case safety report database, VigiBase, to estimate reporting odds ratios of cholangiocarcinoma.

RESULTS:

During 614 274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100 000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively).

CONCLUSION:

Compared with use of other second or third line antidiabetic drugs, use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: this study was funded by the Canadian Institutes of Health Research. RWP received consulting fees for work unrelated to this project from Amgen, Eli Lilly, Merck, and Pfizer. All other authors have no conflicts to disclose, and have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Department of Psychology, University of Southern Denmark, Odense, Denmark.

7

AHP Research, Hornchurch, UK.

Abstract

AIMS:

Prospective memory has been long considered a fundamental cognitive ability for optimal medication taking, but the role of prospective memory errors (termed 'slips') in diabetes self-care is unclear. Our aim was to examine associations between prospective memory and medication taking in adults with Type 1 and Type 2 diabetes mellitus.

METHODS:

Some 901 adults with Type 1 diabetes and 927 with Type 2 diabetes completed a cross-sectional survey focused on the psychological and behavioural aspects of living with diabetes. Respondents reported whether they had forgotten to take their diabetes medication over the previous 14 days.

CONCLUSIONS:

These findings suggest that forgetting medication is relatively common among adults with Type 1 or Type 2 diabetes, and provide preliminary evidence for its relationship with self-reported prospective memory slips.

Abstract

Context and Objective:

Being born small or large for gestational age and intrauterine exposure to gestational diabetes (GDM) increase the risk of type 2 diabetes (T2D) in the offspring, however, the potential combined deleterious effects of size at birth and GDM exposure remains unknown. We aimed to examine the independent effect of size at birth as well as the influence of GDM exposure in utero on cardio-metabolic traits, body composition, and puberty status in children.

Design, Participants and Methods:

This study is a longitudinal birth cohort study. We used clinical data from 490 offspring of mothers with GDM and 527 control offspring aged 9-16 years, born singleton at term from the Danish National Birth Cohort with available birth weight data.

Results:

We found no evidence of a U-shaped association between size at birth (expressed as birth weight, sex and gestational age adjusted z-score) and cardio-metabolic traits. Body size in childhood and adolescence reflected size at birth, but was not reflected in any metabolic outcome. No synergistic adverse effect of being born small or large for gestational age and being exposed to GDM was shown. However, GDM was associated with an adverse metabolic profile and earlier onset of female puberty in childhood and adolescence independently of size at birth.

Conclusion:

In childhood and adolescence, GDM is a stronger predictor of dysmetabolic traits than size at birth. The combination of being born small or large and being exposed to GDM does not exacerbate the metabolic profile in the offspring.

Centre for Bone and Arthritis Research, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

2

Bioinformatics Core Facility, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

3

Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Abstract

Objective:

The aim of this study was to determine the role of change in body mass index (BMI) during puberty, independent of childhood overweight, for the risk of adult type 2 diabetes in men.

Study design, population and outcome:

We included 36,176 men who had weight and height measured at age 8 (childhood) and 20 (young adult age) available from the BMI Epidemiology Study (BEST) and the Conscription register. Information on type 2 diabetes (n=1,777) was retrieved from the Swedish National Patient Register. Hazard ratios and 95% Confidence Intervals were estimated by Cox regressions including birth year and country of birth as covariates. Because the assumption of proportional hazards was violated for the association between BMI change during puberty and type 2 diabetes, we split the follow-up time into early (≤55.7 years) and late (>55.7 years).

Results:

Both childhood overweight and a high BMI increase during puberty associated with risk of adult type 2 diabetes. Men with childhood overweight that normalized during puberty did not have a significantly increased risk of type 2 diabetes (Early type 2 diabetes 1.28[0.89; 1.82]; Late type 2 diabetes 1.35[0.97; 1.87]). Men who developed overweight during puberty (Early 4.67[3.90; 5.58]; Late 2.85[2.25; 3.61]) and men overweight at both childhood and young adult age (Early 4.82[3.84; 6.05]; Late 3.04[2.27; 4.06]) had substantially increased risk of type 2 diabetes compared with men who were never overweight.

Conclusion:

BMI change during puberty is an important, and childhood BMI a modest, independent determinant of adult type 2 diabetes risk in men.

Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane QLD, Australia.

2

Faculty of Biological Sciences, University of Concepción, Concepción, Chile.

3

Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.

4

Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.

Mater Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Abstract

Context:

Molecules produced by adipose tissue (AT) function as an endocrine link between maternal AT and fetal growth by regulating placental function in normal and gestational diabetes mellitus (GDM).

Objective:

We hypothesised that AT-derived exosomes from women with GDM carry a specific set of proteins that influences glucose metabolism in placenta.

Design:

Exosomes were isolated from omental AT-conditioned media from pregnant women with normal glucose tolerance (exo-NGT, n=65) and women with GDM (exo-GDM, n=82). SWATH mass spectrometry (MS) was used to construct a small ion library from AT and exosomal proteins followed by ingenuity pathway analysis (IPA) to determine canonical pathways and biofunctions. The effect of exosomes on human placental cells was determined using a Human Glucose Metabolism RT2 Profiler PCR Array.

Results:

The number of exosomes (vesicles/μg-tissue/24h) was significantly (1.7-fold) higher in GDM compared to NGT, and the number of exosomes positively correlated with birthweight Z score. IPA of the exosomal proteins revealed differential expression of the proteins targeting sirtuin (sirt) signalling pathway, oxidative phosphorylation (OXPHOS) and mechanistic target of rapamycin (mTOR) signalling pathways in GDM compared to NGT. Exo-GDM increased the expression of genes associated with glycolysis and gluconeogenesis in placental cells compared to the effect of exo-NGT.

Conclusions:

Our findings are consistent with the possibility that AT exosomes play an important role in mediating the changes in placental function in GDM, which may be responsible for some of the adverse consequences in this pregnancy complication, such as fetal overgrowth.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

4

Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea.

Abstract

Context:

Body-weight fluctuation (weight cycling) has been found to be associated with higher mortality and cardiovascular events in patients with coronary artery disease. However, there are very limited data regarding the relationship between body-weight fluctuation and health-related outcomes in the general population.

Methods:

We examined whether body-weight fluctuation can associate incident diabetes mellitus and cardiovascular events, and mortality in a Korean population from the Korean Genome and Epidemiology Study. The intraindividual fluctuations of body weight were calculated by average successive variability (ASV); health-related outcomes were collected every 2 years for 16 years in 3,678 participants.

Results:

Participants with a high ASV of body weight were more obese and had higher blood pressure and HbA1c levels at baseline than those with a low ASV of body weight. A 1-unit increase in ASV of body weight was associated with increase in mortality (HR, 1.46; 95% CI, 1.32 to 1.62; P < 0.001). However, the association between the ASV of body weight and incident diabetes mellitus seemed to be influenced by baseline body mass index (BMI): negative effect in subjects with BMI <25 kg/m2 (HR, 1.36; 95% CI, 1.11 to 1.65; P = 0.003) and protective effect in those with BMI ≥25 kg/m2 (HR, 0.76; 95% CI, 0.60 to 0.95; P = 0.014). There was no association between the ASV of body weight and cardiovascular event.

Conclusion:

Body-weight fluctuation was associated with mortality. In addition, the effect of body-weight fluctuation on incident diabetes mellitus depended on the presence of obesity at baseline.